WO2006105811A1 - Composes convenant comme modulateurs de l'activite du proteasome - Google Patents
Composes convenant comme modulateurs de l'activite du proteasome Download PDFInfo
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- WO2006105811A1 WO2006105811A1 PCT/EP2005/013893 EP2005013893W WO2006105811A1 WO 2006105811 A1 WO2006105811 A1 WO 2006105811A1 EP 2005013893 W EP2005013893 W EP 2005013893W WO 2006105811 A1 WO2006105811 A1 WO 2006105811A1
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- FOMIHTTUAILLQT-ZDUSSCGKSA-N methyl (2s)-3-(4-methoxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(=O)OC)CC1=CC=C(OC)C=C1 FOMIHTTUAILLQT-ZDUSSCGKSA-N 0.000 description 1
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
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- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical class OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 description 1
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- MBQKTLYFUYNAPZ-FEZMQHRXSA-N ra vii Chemical compound C1=CC(OC)=CC=C1C[C@H](N(C)C(=O)[C@H](C)NC(=O)[C@@H](C)NC(=O)[C@@H](N(C1=O)C)C2)C(=O)N[C@@H](C)C(=O)N(C)[C@H]1CC(C=C1)=CC=C1OC1=CC2=CC=C1OC MBQKTLYFUYNAPZ-FEZMQHRXSA-N 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- IWUYVKKHPNFWJG-UHFFFAOYSA-N spirotryptostatin B Natural products O=C1NC2=CC=CC=C2C21C=C(C(=O)N1C(CCC1)C1=O)N1C2C=C(C)C IWUYVKKHPNFWJG-UHFFFAOYSA-N 0.000 description 1
- 238000011255 standard chemotherapy Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QWWUUJBDSFYDPX-SVWSIEHRSA-N tert-butyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-(benzylamino)-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]-1-oxohexan-2-yl]amino]-1-oxo-3-(4-phenylmethoxyphenyl)propan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC=1C=CC=CC=1)NC(=O)OC(C)(C)C)C(C=C1)=CC=C1OCC1=CC=CC=C1 QWWUUJBDSFYDPX-SVWSIEHRSA-N 0.000 description 1
- CFGSTPXLBKGTCY-SIWBJXOXSA-N tert-butyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-anilino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-(4-phenylmethoxyphenyl)propan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NC=1C=CC=CC=1)NC(=O)OC(C)(C)C)C(C=C1)=CC=C1OCC1=CC=CC=C1 CFGSTPXLBKGTCY-SIWBJXOXSA-N 0.000 description 1
- RBUADDGIWPXAKP-IGMOWHQGSA-N tert-butyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-anilino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-(4-phenylmethoxyphenyl)propan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NC=1C=CC=CC=1)NC(=O)OC(C)(C)C)C(C=C1)=CC=C1OCC1=CC=CC=C1 RBUADDGIWPXAKP-IGMOWHQGSA-N 0.000 description 1
- NAYUZUWDCPQMLZ-BJKOEGOMSA-N tert-butyl n-[(2s)-1-[[(2s)-1-[[(2s)-1-anilino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]-1-oxohexan-2-yl]amino]-1-oxo-3-(4-phenylmethoxyphenyl)propan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NC=1C=CC=CC=1)NC(=O)OC(C)(C)C)C(C=C1)=CC=C1OCC1=CC=CC=C1 NAYUZUWDCPQMLZ-BJKOEGOMSA-N 0.000 description 1
- LTUPMZVMJNDKLO-HRSOTDIYSA-N tert-butyl n-[(2s)-1-[[(2s)-1-[[(2s)-3-(1h-indol-3-yl)-1-[4-[(2-methylpropan-2-yl)oxycarbonylamino]butylamino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-(4-phenylmethoxyphenyl)propan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(C=C1)=CC=C1OCC1=CC=CC=C1 LTUPMZVMJNDKLO-HRSOTDIYSA-N 0.000 description 1
- JWACGQCPTSCPCR-SVWSIEHRSA-N tert-butyl n-[(2s)-1-[[(2s)-1-[[(2s)-3-(1h-indol-3-yl)-1-[4-[(2-methylpropan-2-yl)oxycarbonylamino]butylamino]-1-oxopropan-2-yl]amino]-6-[(2-methylpropan-2-yl)oxycarbonylamino]-1-oxohexan-2-yl]amino]-1-oxo-3-(4-phenylmethoxyphenyl)propan-2-yl]carbamate Chemical compound C([C@@H](C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(C=C1)=CC=C1OCC1=CC=CC=C1 JWACGQCPTSCPCR-SVWSIEHRSA-N 0.000 description 1
- KIBNRUYHBFFAEK-FSEITFBQSA-N tert-butyl n-[(2s)-1-[[(2s)-4-amino-1-[[(2s)-1-(benzylamino)-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxo-3-(4-phenylmethoxyphenyl)propan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC=1C=CC=CC=1)C(C=C1)=CC=C1OCC1=CC=CC=C1 KIBNRUYHBFFAEK-FSEITFBQSA-N 0.000 description 1
- FVZIJECGRZTKSE-KVBYWJEESA-N tert-butyl n-[(2s)-1-[[(2s)-4-amino-1-[[(2s)-1-anilino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxo-3-(4-phenylmethoxyphenyl)propan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NC=1C=CC=CC=1)C(C=C1)=CC=C1OCC1=CC=CC=C1 FVZIJECGRZTKSE-KVBYWJEESA-N 0.000 description 1
- UXTUYGBBMMWNFI-ZPGRZCPFSA-N tert-butyl n-[(2s)-1-[[2-[[(2s)-1-(benzylamino)-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-(4-phenylmethoxyphenyl)propan-2-yl]carbamate Chemical compound C([C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC=1C=CC=CC=1)C(C=C1)=CC=C1OCC1=CC=CC=C1 UXTUYGBBMMWNFI-ZPGRZCPFSA-N 0.000 description 1
- ZFQUJHPCHFSVMH-MXVPUGLGSA-N tert-butyl n-[4-[[(2s)-3-(1h-indol-3-yl)-2-[[(2s)-4-methyl-2-[[(2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(4-phenylmethoxyphenyl)propanoyl]amino]pentanoyl]amino]propanoyl]amino]butyl]carbamate Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(C=C1)=CC=C1OCC1=CC=CC=C1 ZFQUJHPCHFSVMH-MXVPUGLGSA-N 0.000 description 1
- HGYZWHLXRIKILA-UHFFFAOYSA-N tert-butyl oxaziridine-2-carboxylate Chemical class CC(C)(C)OC(=O)N1CO1 HGYZWHLXRIKILA-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
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- 238000006257 total synthesis reaction Methods 0.000 description 1
- 108010039189 tripeptidyl-peptidase 2 Proteins 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 150000003653 tryptophane derivatives Chemical class 0.000 description 1
Classifications
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- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
- A61K8/492—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid having condensed rings, e.g. indol
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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Definitions
- the present invention relates to compounds active as modulators (inhibitors or activators) of the proteasome activity in mammals, including man, to their process for their preparation, and to their uses for the treatment of pathologies involving the proteasome.
- the ubiquitin-proteasome system is the major pathway of proteolysis in eukaryotic cells (Ciechanover, A. EMBO J, 1998, 17, 7151-7160).
- the eukaryotic proteasome 26S (2.4 MDa) is a multicatalytic protease consisting of a 2OS proteolytic core particle and a 19S regulatory subunit at either or both ends (Groll, M.; Huber, R.
- the multifunctional complex is composed of at least 44 polypeptides and has unique properties. Among them, we can point out the 6 active sites (two of chyrnotryptic-, two of tryptic- and two of caspase-like activities) which are segregated in a secluded compartment which favours a processive degradation of proteins.
- Proteasome is also a N-terminal threonine hydrolase.
- Proteasome 26S recognizes polyubiquinated protein and is ATP-dependent. Mammalian cells contain another regulatory complex that associates with the 2OS proteasome: the I IS regulator or PA28 which promotes the production of antigenic peptides.
- the 20S proteasome degrades oxidized proteins (Davies K. J. A. Biochimie, 2001 , 301-310) and also an increasing amount of non ubiquitinylated proteins such as the proto-oncogenic c-Fos protein (Bossis G., Frerrar P., Acquaviva C, Jariel-Encontre L, Piechaczyk M. MoI. Cell. Biol. 2003, 23, 7425-7436).
- proteasomes are found in both the nucleus and the cytoplasm of eukaryotic cells, hi the cytoplasm, proteasomes localize near centrosomes, on the outer surface of the endoplasmic reticulum and in cytoskeletal networks. hi addition to removing of damaged and unneeded proteins, proteasome degrades key regulatory proteins, which are crucial for many intracellular processes, including cell progression, apoptosis, NF- ⁇ B activation and antigen presentation (Coux, O. ; Tanaka, K. ; Goldberg, A. L. Annu. Rev. Biochem. 1996, 65, 801-847; Ciechanover, A. EMBO J., 1998, 17, 7151-7160).
- proteasome substrates are known mediators of pathways that are dysregulated with neoplasia (Adams J. Cancer- Cell 2003, 5, 417- 421 ; Adams J. Nature Reviews/Cancer 2004, 4, 349-359). Proteasome affects cell- cycle progression by regulating the cyclins, and increasing or decreasing the apoptotic activity through effects on caspases, Bcl2 activity and nuclear factor NF- ⁇ B.
- an empirical finding is that malignant cells are more susceptible to certain proteasome inhibitors than normal cells: reversal or bypass of some of the effects of the mutations in cell-cycle and apoptotic checkpoints that have led to tumorigenesis; higher dependency of malignant cells to proteasome system to remove aberrant proteins, dependence of some tumors to maintain drug or radiation resistance
- proteasome inhibitors are reported to enhance sensitivity to standard chemotherapy, radiationjherapy or immunotherapy, and to overcome drug resistance.
- NF- ⁇ B is activated by radiotherapy and chemotherapy in malignant tissues and proteasome inhibition blocks NF- ⁇ B activation by preventing proteasomal degradation of I KB (Cusak. Jr et al. . Cancer Res. , 2001, 61, 3535-3540).
- Bortezomib is the first proteasome inhibitor to be approved for the treatment of multiple myeloma based on several types of data : direct inhibition of cancer cells, interference with the adhesion of multiple myeloma cells to bone marrow stroma cells and with production 11-6 in the bone marrow, anti-angiogenic properties (Adams J.
- Bortezomib is administered as cyclical therapy (twice-weekly treatment for 2 weeks every 3 weeks). Proteasome activity is maximally inhibited over 1 h after dosing (Orlowski RZ et al. J. CHn. Oncol. 2002, 20, 4420-4427). Adverse events have been reported in 30% patients enrolled in clinical trials (thrombocytopaenia, fatigue, peripheral neuropathy and neutropenia). Trials are in progress to investigate the use of bortezomib alone or in numerous combinations in order to evaluate its therapeutic value in various cancers (solid and liquid tumors). Results on non-Hodgin's lyphoma, colorectal, lung, breast and prostate cancers appear to be encouraging.
- the natural epoxyketones (epoxomicin and eponemicin) have the unique particularity to react with O ⁇ and Ot-NH 2 of Thrl.
- Non covalent inhibitors have been investigated less extensively, and in principle, should lower side-effects. Only three classes of such inhibitors are known.
- Ritonavir Schomtke, G.; Holzh ⁇ tter, H.-G.; Bogyo, M.; Kairies, N.; Groll, M.; De Giuli, R.; Emch, S.; Groettrup, M. J Biol. Chem. 1999, 274, 35734-35740
- benzylstatine derivatives Furet, P.; Imbach, P.; Noorani, M.; Koeppler J.; Laumen, K.; Lang, M.;
- a cyclic peptide TMC-95A which is a metabolite of Apiospora currentlyi is a potent reversible inhibitor with no inhibition of m-calpain, cathepsin-L and trypsin (Onuki, T.; Sugita, N., Kono, O.; Kogushi, Y.; Murakami, T.; Nishio, M., (Tanabe Seiyaku Co., Ltd) JP 11029595; 1999.; Koguchi, Y.; Kohno, J.; Nishio, M.; Takahashi, K.; Okuda, T.; Ohnuki, T.; Komatsubara, S., J Antibiot (Tokyo) 2000, 53, (2), 105-9.
- TMC-95 Some macrocyclic derivatives of TMC-95 were prepared and were shown to be non covalent inhibitors of proteasome (Kaiser, M.; Groll, M.; Renner, C; Huber, R.; Moroder, L., Angew. Chem. Int. Ed. 2002, 41, (5), 780-783 ; Kaiser, M.; Siciliano, C;
- proteasome inhibitors are potential drugs by retarding or blocking the degradation of specific proteins in disorders associated with their excessive degradation.
- Proteasome activators are susceptible to favor degradation of oxidized proteins and prevent the formation of protein aggregates as observed in Alzheimer's and
- the main goal of the present invention is to provide new compounds acting as modulators of the proteasome activity (inhibitors or activators), and having the following advantages when compared to the prior art compounds mentioned above : a. they are mild, controllable and reversible inhibitors, with no creation of a covalent bond between the enzyme and the inhibitor.
- proteasome Due to the implication of proteasome in a large variety of physiological processes, an irreversible permanent inhibition of proteasome would likely be detrimental. b. they are low-molecular-weight molecules and their synthetic routes are simple; c. they have a differential selectivity towards the three kinds of active sites.
- the invention relates to the use of compounds of the following general formula (I) ;
- Rj 0 is a linear or branched alkyl group from 1 to 5 carbon atoms
- R 11 is a linear or branched alkyl group from 1 to 5 carbon atoms, an aryl group, possibly substituted, NH 2 , or NEIR 12 in which R 12 is a protecting group of amine functions, such as the tertiobutyloxycarbonyl (Boc) group, or the CO-O-CH 2 - C 6 H 5 (Z) group, - R 2 is :
- n 2 is an integer from 1 to 5
- R 3 is H, or a linear or branched alkyl group from 1 to 5 carbon atoms, optionally substituted with an aryl group,
- R 4 is H, or a protecting group of amine functions, such as Boc, or Z,
- - R 5 is H, or a protecting group of amine functions, such as Boc, or Z
- - R 6 is a OR 16 group in which R 16 is a linear or branched alkyl group from 1 to 5 carbon atoms,
- R 7 and R 8 independently from one another, are H, or a halogen atom, such as Br, I, or Cl, as modulators of the proteasome activity, in the frame of the preparation of a medicament useful for the prevention or treatment of diseases wherein the proteasome is involved, or the preparation of cosmetic compositions, or of phytosanitary compositions.
- a halogen atom such as Br, I, or Cl
- inhibitors of the proteasome activity are: - either inhibitors of the proteasome activity, i.e. have the following inhibition properties against chymotrypsin-like, or/and trypsin-like, or/and post-acid activities of rabbit 2OS proteasome which can be measured using the appropriate fluorogenic substrate, as described below : initial rates determined in control experiments (without test compound) were considered to be 100 % of the peptidasic activity, initial rates below 100 % were considered to be inhibitions,
- activators of the proteasome activity i.e. have the following activation properties against chymotrypsin-like, or/and trypsin-like, or/and post-acid activities of rabbit 2OS proteasome, which can be measured using the appropriate fluorogenic substrate as described below ; initial rates that were above 100 % in the presence of a test compound were considered to be activators.
- R 1 , R 2 , R 3 , and R 4 are such as defined above.
- the invention relates more particularly to the use as defined above of compounds of formula (II) in which :
- R 1 is a group OR 10 in which Ri 0 is a linear or branched alkyl group from 1 to 5 carbon atoms,
- R 2 is a linear or branched alkyl group from 1 to 5 carbon atoms
- R 3 is a linear or branched alkyl group from 1 to 5 carbon atoms, optionally substituted with an aryl group,
- R 4 is a protecting group of amine functions, such as Boc.
- R 1 is OCH 3 ,
- R 2 is CH 3 , or CH 2 -CH-(CH 3 ) 2 ,
- R 3 is CH 3 , or CH 2 -C 6 H 5 ,
- R 1 is OCH 3
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 3
- R 4 is Boc (compound A374F1)
- R 1 is OCH 3
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound A291)
- R 1 is OCH 3
- R 2 and R 3 are CH 3
- R 4 is Boc (compound A389Fl ⁇ l2).
- R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are such as defined above.
- the invention relates more particularly to the use as defined above of compounds of formula (III) in which:
- R 2 is a linear or branched alkyl group from 1 to 5 carbon atoms
- R 3 is a linear or branched alkyl group from 1 to 5 carbon atoms, optionally substituted with an aryl group,
- R 4 is a protecting group of amine functions, such as Boc,
- R 5 is a protecting group of amine functions, such as Z,
- R 16 is a linear or branched alkyl group from 1 to 5 carbon atoms.
- the invention also relates more particularly to the use as defined above of compounds of formula (III) in which :
- Ri is OCH 2 CH 3 , OrNHCH 3 ,
- R 2 is CH 3 , or CH 2 -CH-(CH 3 ) 2 ,
- R 3 is CH 2 -C 6 H 5 ,
- R 6 is OCH 3 .
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 5 is Z
- R 6 is OCH 3 (compound SP221)
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 5 is Z
- R 6 is OCH 3 (compound SP225F2)
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 5 is Z
- R 6 is OCH 3 (compound SP226F1).
- R 3 is a linear or branched alkyl group from 1 to 5 carbon atoms, optionally substituted with an aryl group,
- R 4 is a protecting group of amine functions, such as Boc,
- R 7 and Rg independently from one another, are a halogen atom, such as Br, I.
- the invention concerns more particularly the use as defined above of compounds of formula (IV-I) in which :
- - Ri is OH, OCH 3 , OCH 2 CH 3 , Or NHCH 3 ,
- R 2 is H, CH 3 , CH 2 -CH-(CH 3 ) 2 ,or CH 2 CONH 2 ,
- R 3 is CH 3 , or CH 2 -C 6 H 5 ,
- R 1 is OCH 3
- R 2 ' is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A248), or
- R 1 is OH
- R 2 is CH 3
- R 3 is CH 2 -C 6 Hs
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A215), or
- R 1 is OCH 3
- R 2 is CH 2 CONH 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound SP274), or
- R 1 is OCH 3
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is GH 3
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A363), or
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 3
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A340), or
- R 1 is OCH 2 CH 3
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 7 is I
- Rg is Br (compound Al 74), or
- R 1 is OCH 3
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A268), or
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is CH 3
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A385), or
- R 1 is NHCH 3
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A254).
- Preferred compounds of formula (IV-Ia) used in the frame of the present invention are compounds A215, SP274 and A254.
- the invention relates more particularly to the use as defined above of compounds of the following formula (IV-Ib) :
- R 1 is OCH 3
- R 2 is H
- R 3 is CH 3
- R 4 is Boc
- R 7 is I
- R 8 is Br
- X CH 2 (compound A493), or
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is CH 3
- R 4 is Boc
- R 7 is I
- R 8 is Br
- X NCH 2 C 6 H 5 .
- the invention also relates to the use of compounds of formula (IV) as defined above wherein R 7 and R 8 are H.
- R 3 is H, or a linear or branched alkyl group from 1 to 5 carbon atoms, optionally substituted with an aryl group,
- R 1 is OH, OCH 3 , NHCH 2 C 6 H 5 , NHC 6 H 5 , NHC 6 H 4 OH, or NH(CH 2 ) 4 NHBoc,
- the invention relates more particularly to the use as defined above of compounds of formula (IV-2) in which : - R 1 is NHCH 2 C 6 H 5 , R 2 is H, R 3 is CH 2 -C 6 H 5 , and R 4 is Boc (compound
- R 1 is OH
- R 2 is H
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound NR35)
- R 1 is NHC 6 H 5
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP303r2)
- - or R 1 is NHCH 2 C 6 H 5
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 1 is NHC 6 H 4 OH
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP313P)
- R 1 is NH(CH 2 ) 4 NHBoc
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP305R)
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound NR36)
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is H
- R 4 is Boc (compound NR40)
- R 1 is NHC 6 H 5
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound A424P)
- - or R 1 is NHCH 2 C 6 H 5
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 1 is NHC 6 H 4 OH
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound A418P)
- R 1 is NH(CH 2 ) 4 NHBoc
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP296P)
- R 1 is NHC 6 H 5
- R 2 is CH 2 CONH 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP314C2)
- R 1 is NHCH 2 C 6 H 5
- R 2 is CH 2 CONH 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound A416)
- - or R 1 is NHC 6 H 4 OH
- R 2 is CH 2 CONH 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 1 is NH(CH 2 ) 4 NHBoc
- R 2 is CH 2 CONH 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP323C2)
- - or R 1 is NHC 6 H 5
- R 3 is H
- R 4 is Boc (compound SP325)
- R 1 is NHC 6 H 4 OH
- R 3 is H
- R 4 is Boc (compound SP324)
- - or R 1 is NHC 6 H 5
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 1 is NHCH 2 C 6 H 5
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP315C2)
- R 1 is NHC 6 H 4 OH
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP320P2)
- R 1 is NH(CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP311C)
- R 1 is NHC 6 H 5
- R 2 is (CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP306P)
- - or R 1 is NHCH 2 C 6 H 5
- R 2 is (CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 1 is NHC 6 H 4 OH
- R 2 is (CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP319P)
- R 1 is NH(CH 2 ) 4 NHBoc
- R 2 is (CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP308P).
- R 1 is OH
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound NR66).
- R 1 is OH
- R 2 is CH 3
- R 3 is H
- R 4 is Boc (compound NR68).
- Preferred compounds of formula (IV-2) used in the frame of the present invention are the compounds SP313P, NR40, SP325, and SP324.
- the invention also concerns the use as defined of compounds of the following formula (IV-3) :
- Rg is an oxygen atom O
- R 3 is H, or a linear or branched alkyl group from 1 to 5 carbon atoms, optionally substituted with an aryl group,
- the invention relates more particularly to the use as defined above of compounds of formula (IV-3) in which :
- R 1 is OH, OCH 3 , NHCH 2 C 6 H 5 , or NHC 6 H 5 ,
- R 3 is H, or CH 2 -C 6 H 5 ,
- R 1 is NHC 6 H 5
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound CVl 1)
- - R 1 is NHC 6 H 5
- R 2 is (CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 1 is NHC 6 H 5
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound CV13)
- - Ri is NHC 6 H 5
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound JV602)
- - Ri is NHCH 2 C 6 H 5
- R 2 is H
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound NRl 5)
- - Ri is NHCH 2 C 6 H 5
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound NRl 6)
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- - Ri is OH
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- - Ri is OH
- R 2 is CH 3
- R 3 is H
- R 4 is Boc
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is H
- R 4 is Boc
- Preferred compounds of formula (IV-3) used in the frame of the present invention are the compounds CV12, CV13, NR15, and NR38.
- the invention relates more particularly to the use of a compound as defined above, as modulators of the proteasome activity for the preparation of:
- pathologies involving proteasome said pathologies being chosen from the group constituted by: cancers involving haematological or solid tumors, immunological diseases, auto-immune diseases, AIDS, inflammatory diseases, cardiac pathologies and consequences of ischemic processes in myocardial, cerebral or pulmonary regions, allograft rejection, myopathies, muscle wasting, cerebrovascular accidents, traumatisms, burns, pathologies associated with aging like Alzheimer's disease and Parkinson's disease, and the appearance of aging signs, or - a drug for increasing the radiosensitization of a tumor, the sensitivity to chemotherapy and/or immunotherapy, or promoting the circumvention of resistances, or
- a cosmetic composition for the implementation of a method of cosmetic prevention or treatment of the appearance of cutaneous aging and/or photoaging, or o
- phytosanitary compositions for the implementation of processes for modulating the defence response of plants, in particular phytosanitary compositions for the stimulation of plants defence response against phytopathogenic agents.
- compositions or drags used in the frame of the present invention comprise compounds as defined above mainly acting as inhibitors of the proteasome activity.
- Preferred compounds contained in the pharmaceutical compositions as defined above are those of formula IV-IA, or TV-2, or IV-3, or IV-IB such as compounds A215, SP274, A254, or SP313P, NR40, SP325, SP324, or CV12, CV13, NR15, NR38, or A493.
- compositions used in the frame of the present invention comprise compounds as defined above mainly acting as activators of the proteasome activity.
- Preferred compounds contained in the cosmetic compositions as defined above are those of formula II, or III, or IV-IA, or IV-2, or IV-3, or TV-IB such as compounds
- compositions used in the frame of the present invention comprise compounds as defined above mainly acting as inhibitors of the proteasome activity.
- Preferred compounds contained in the phytosanitary compositions as defined above are those of formula formula IV-IA, or IV-2, or IV-3, or IV-IB such ' as compounds A215, SP274, A254, or SP313P, NR40, SP325, SP324, or CV12, CV13, NR15, NR38, or A493.
- the invention also concerns a pharmaceutical composition, characterized in that it comprises a compound as defined above, in association with a pharmaceutically acceptable vehicle.
- the invention relates more particularly to the pharmaceutical composition as defined above, characterized in that it contains a compound as defined above, at an appropriate amount for a daily administration of about twice a week for 4 weeks at about 1.5 mg/m 2 .
- the invention also relates more particularly to the pharmaceutical composition as defined above, characterized in that it is in a form suitable for intravenous or per os administration.
- the invention also concerns a cosmetic composition characterized in that it comprises a compound as defined above, in association with a pharmacologically acceptable vehicle.
- the invention relates more particularly to the cosmetic composition as defined above, characterized in that it is in a form suitable for dermatological administration, in particular as a cream, pomade or gel.
- the invention concerns more particularly the cosmetic composition as defined above, characterized in that it contains a compound as defined above, at an appropriate amount for a daily administration of about 1 mg/m to 10 mg/m of skin.
- the invention also concerns a phytosanitary composition, characterized in that it comprises a compound as defined above, if necessary in association with an acceptable vehicle in phytosanitary field.
- the invention relates more particularly to the phytosanitary composition as defined above, characterized in that it comprises a compound as defined above, at an appropriate amount for an administration by spraying of about 1 g/m 2 to 10 g/m 2 .
- the invention also concerns the compounds of formula (I), and more particularly of formula (II), (III), and (IV) as defined above.
- the invention also relates to compounds of the following formula (III) :
- - R 2 is a linear or branched alkyl group from 1 to 5 carbon atoms
- - R 3 is a linear or branched alkyl group from 1 to 5 carbon atoms, optionally substituted with an aryl group
- R 4 is a protecting group of amine functions, such as Boc,
- R 5 is a protecting group of amine functions, such as Z,
- R 6 is a OR 16 group in which R 16 is a linear or branched alkyl group from 1 to 5 carbon atoms.
- the invention also relates more particularly to compounds of formula (III) as defined above in which :
- R 1 is OCH 2 CH 3 , OrNHCH 3 ,
- R 2 is CH 3 , or CH 2 -CH-(CH 3 ) 2 , - R 3 Is CH 2 -C 6 H 5 ,
- - R 5 is Z
- - R 6 is OCH 3 .
- the invention concerns more particularly the compounds of formula (III) as defined above in which :
- R 1 is OCH 2 CH 3
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 5 is Z
- R 6 is OCH 3 (compound SP221)
- R 1 is NHCH 3
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 5 is Z
- R 6 is OCH 3 (compound SP225F2)
- - or R 1 is NHCH 3
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 5 is Z
- and R 6 is OCH 3 (compound SP225F2)
- R 6 is OCH 3 (compound SP226F1).
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5 (compound A248), or
- R 2 is CH 2 CONH 2
- R 3 is CH 2 -C 6 H 5 (compound SP274), or
- R 2 is CH 2 -CH-(CH 3 );.
- R 3 is CH 3 (compound A363), or
- R 2 is CH 2 -CH-(CHs) 2
- R 3 is CH 2 -C 6 H 5 (compound A268), being exluded.
- the invention relates more particularly to compounds as defined above, of the following formula (IV-I) :
- R 3 is a linear or branched alkyl group from 1 to 5 carbon atoms, optionally substituted with an aryl group,
- R 4 is a protecting group of amine functions, such as Boc,
- R 7 and R 8 independently from one another, are a halogen atom, such as Br, I.
- the invention concerns more particularly compounds of formula (IV-I) as defined above in which :
- R 1 is OH, OCH 3 , OCH 2 CH 3 , OrNHCH 3 ,
- R 2 is H, CH 3 , CH 2 -CH-(CH 3 ) 2 ,or CH 2 CONH 2 ,
- R 3 is CH 3 , or CH 2 -C 6 H 5 ,
- the invention relates more particularly to compounds as defined above, of the following formula (IV-Ia):
- the invention also relates more particularly to compounds of formula (IV-Ia) as defined above in which :
- R 1 is OH
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A215)
- R 1 is OCH 2 CH 3
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 3
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A340)
- R 1 is OCH 2 CH 3
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound Al 74)
- Ri OCH 3
- R 2 is CH 3
- R 3 is CH 3
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A385)
- R 1 is NHCH 3
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 7 is I
- R 8 is Br (compound A254).
- the invention relates more particularly to compounds as defined above of the following formula (W-Ib):
- the invention concerns more particularly compounds of formula (IV-Ib) as defined a bove in which
- R 1 is OCH 3
- R 2 is H
- R 3 is CH 3
- R 4 is Boc
- R 7 is I
- R 8 is Br
- X CH 2 (compound A493), or
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is CH 3
- R 4 is Boc
- R 7 is I
- R 8 is Br
- X NCH 2 C 6 H 5 .
- the invention also relates to compounds of formula (IV) as defined above wherein R 7 and R 8 are H.
- the invention also concerns compounds as defined above of the following formula (IV-2) :
- R 3 is H, or a linear or branched alkyl group from 1 to 5 carbon atoms, optionally substituted with an aryl group,
- R 4 is a protecting group of amine functions, such as Boc,
- the invention relates more particularly to compounds of formula (IV-2) as defined above in which :
- R 3 is H, or CH 2 -C 6 H 5 ,
- R 1 is NHCH 2 C 6 H5, R 2 is CH 3 , R 3 is CH 2 -C 6 H 5 , and R 4 is Boc (compound SP304R),
- R 1 is NHC 6 H 4 OH
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP313P)
- R 1 is NH(CH 2 ) 4 NHBoc
- R 2 is CH 3
- R 3 is CH 2 -C 5 H 5
- R 4 is Boc (compound SP305R)
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound NR36)
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is H
- R 4 is Boc (compound NR40), - or R 1 is NHC 6 H 5
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 1 is NH(CH 2 ) 4 NHBoc
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP296P)
- R 1 is NHC 6 H 5
- R 2 is CH 2 CONH 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP314C2)
- - or Ri is NHCH 2 C 6 H 5
- R 2 is CH 2 CONH 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 1 is NHC 6 H 4 OH
- R 2 is CH 2 CONH 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP318C)
- - or R 1 is NH(CH 2 ) 4 NHBoc
- R 2 is CH 2 CONH 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP323C2)
- R 1 is NHC 6 H 5
- R 3 is H
- R 4 is Boc (compound SP325)
- - or R 1 is NHC 6 H 4 OH
- R 3 is H
- R 4 is Boc
- R 1 is NHC 6 H 5
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP31 OC)
- R 1 is NHCH 2 C 6 H 5
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP315C2)
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP320P2)
- R 1 is NH(CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP311C)
- - or R 1 is NHC 6 H 5
- R 2 is (CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 1 is NHCH 2 C 6 H 5
- R 2 is (CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP307P)
- R 1 is NHC 6 H 4 OH
- R 2 is (CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP319P)
- R 1 is NH(CH 2 ) 4 NHBoc
- R 2 is (CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound SP308P).
- R 1 is OH
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound NR66).
- R 1 is OH
- R 2 is CH 3
- R 3 is H
- R 4 is Boc (compound NR68).
- the invention relates more particularly to compounds SP313P, NR40, SP325, and
- the invention also concerns compounds as defined above, of the following formula (IV-3) :
- Rg is an oxygen atom O
- R 1 is OH, or a group OR 1 O in which R 1 O is a linear or branched alkyl group from 1 to 5 carbon atoms, or a group of formula NH-(CH 2 ) nl -R ⁇ in which ⁇ ⁇ - 0, or an integer from 1 to 5, and R 11 is an aryl group, possibly substituted,
- R 3 is H, or a linear or branched alkyl group from 1 to 5 carbon atoms, optionally substituted with an aryl group,
- the invention relates more particularly to compounds of formula (IV-3) as defined above in which :
- R 1 is OH, OCH 3 , NHCH 2 C 6 H 5 , OrNHC 6 H 5 ,
- R 3 is H, or CH 2 -C 6 H 5 ,
- the invention also relates more particularly to compounds of formula (IV-3) as defined above in which :
- R 1 is NHC 6 H 5
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound CVIl)
- - R 1 is NHC 6 H 5
- R 2 is (CH 2 ) 4 NHBoc
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- R 1 is NHC 6 H 5
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound CV13)
- R 1 is NHC 6 H 5
- R 2 is CH 2 -CH-(CH 3 ) 2
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound JV602)
- - R 1 is NHCH 2 C 6 H 5
- R 2 is H
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound NRl 5)
- R 1 is OCH 3
- R 2 is H
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound NR38)
- R 1 is NHCH 2 C 6 H 5
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc (compound NRl 6)
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- - R 1 is OH
- R 2 is CH 3
- R 3 is CH 2 -C 6 H 5
- R 4 is Boc
- - Ri is OH
- R 2 is CH 3
- R 3 is H
- R 4 is Boc
- R 1 is OCH 3
- R 2 is CH 3
- R 3 is H
- R 4 is Boc
- the invention relates more particularly to compounds CV12, CV13, NR15, and NR38, as preferred compounds of formula (IV-3).
- Advantageously compounds of formula (II), (III), (IV-I), (IV-2), and (IV-3) as defined above are obtained according to the following retrosynthetic scheme :
- Z-7-bromo-Trp(Boc)-OtBu (2.69 g, 4.69 g, obtained as described for Z-(7-bromo)Trp-OH) was dissolved in a HCl/AcOEt/EtOH mixture and allowed to react for 21 h. Evaporation of the solvent to dryness gave the crude Z-(7-bromo)Trp-OEt which was purified by flash chromatography on silica gel (3% MeOH/CH 2 Cl 2 ) (1.44 g, 70%).
- Z-Trp-NHPh To a solution of Z-Trp-OH (2 g, 5.9 mmol) in THF (88 mL) at 5 0 C were added aniline (540 ⁇ L, 5.9 mmol) and DCC (1.6 g, 7.7 mmol). The reaction was allowed to warm up to room temperature overnight. The solvent was evaporated off and the crude was triturated with ethyl acetate (50 mL). After filtration, the organic phase was successively washed with aqueous 5% KHSO 4 , aqueous 10% KHCO 3 , brine and was dried over Na 2 SO 4 .
- Z-Trp-NH(CH 2 ) 4 NHBoc To a solution of Z-Trp-OH (1 g, 3 mmol) in DMF (16 mL) at 0 °C were added HOBt (611 mg, 4.52 mmol), EDC (636 mg, 3.32 mmol) and NEt 3 (0.5 mL). The reaction was stirred for 30 min followed by drop wise addition of a solution of amine NH 2 (CH 2 ) 4 NHBoc (prepared according to: Krapcho, A. P.; Kuell, C. S., Mono-protected diamines.
- Trp-NHPh A Schlenk flask charged with Z-Trp-NHPh (1.7 g, 4.11 mmol) and 10% Pd/C (437.4 mg) was flushed under H 2 before adding MeOH/DMF (41 rnL, 1/1). The reaction mixture was stirred under atmosphere of H 2 overnight followed by filtration through a pad of celite. The solvent was removed in vacuo and the crude was purified by flash column chromatography on silica gel (2-8% MeOH/CH 2 Cl 2 ). The amine was isolated as a yellow solid (841 mg, 73%). mp 114-116 0 C.
- Trp-NHCH 2 Ph Same procedure as above with Z-Trp-NHCH 2 Ph (616 mg, 1.44 mmol), 10% Pd/C (153 mg) in MeOH/DMF (14.5 mL, 1/1). After purification by flash chromatography on silica gel (3-12% MeOH/CH 2 Cl 2 ), Trp-NHCH 2 Ph was isolated as a pale yellow oil (351 mg, 83%).
- Trp-NH(4-OH)Ph Same procedure as above with Z-Trp-NHPhOH (208 nig, 0.48 mmol), 10% Pd/C (52 mg) in MeOH (5 mL). A light brown solid was obtained after precipitation in CH 2 Cl 2 MeOH (85 mg, 59%).
- Trp-NH(CH 2 ) 4 NHBoc Same procedure as above with Z-Trp-NH(CH 2 ) 4 NHBoc (1.16 g, 2.28 mmol), 10% Pd/C (242 mg) in MeOH/DMF (10 mL, 1/1). After purification by flash chromatography on silica gel (4-25% MeOH/CH 2 Cl 2 ), Trp-NH(CH 2 ) 4 NHBoc was isolated as a white foam (701 mg, 82%).
- L-Z-Trp[O]-OH To a solution of L-H-Trp[O] -OH (2.55 g, 11.57 mmol, prepared according to : Labroo, R. B.; Cohen, L. A., Preparative separation of the diastereoisomers of dioxindolyl-L-alanine and assignment of stereochemistry at C-3. J. Org. Chem. 1990, 55, (16), 4901-4904) in DMF (11.5 mL) was added ZOSu (2.89 g, 11.6 mmol) and then NEt 3 (1.63 mL, 11.7 mmol). The solution was stirred for 4 h at room temperature and then was concentrated in vacuo.
- L-Z-Trp[O]-NHPh To a solution of crude L-Z-Trp[O] -OH (2.22 g, 6.26 mmol) in DME (12.5 mL) was added at O 0 C N-hydroxysuccinimide (0.757 g, 6.58 mmol) and dicyclohexylcarbodiimide (1.36 g, 6.58 mmol). After 15 min at 0 °C, the mixture was stirred at room temperature overnight. The white solid was filtered and washed by DME (3 X 5 mL).
- L-Z-Trp [O]-NHCH 2 Ph Same procedure as above starting from Z-Trp-OSu (1.54 g, 3.29 mmol) and benzylamine (0.43 mL, 3.95 mmol) afforded L-Z-Trp[O]-NHCH 2 Ph after recristallization in EtOH (0.775 g, 53%) as a white solid.
- Dipeptides were prepared using conventional peptide synthesis and were obtained according to Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J., Synthesis of macrocyclic peptide analogues of proteasome inhibitor TMC-95 A. J. Org. Chem. 2003, 68, (25), 9835-9838.
- N-Boc ⁇ Tyr(Me) ⁇ AIa-OMe N-Boc ⁇ Tyr(Me) ⁇ AIa-OMe:. This compound was synthesized as described above from N- Boc-Tyr(Me)-OSu (1 g, 2.55 mmol), HCl, AIa-OMe (320.5 mg, 2.3 mmol) and NEt 3 (323 ⁇ L, 2.3 mmol). The dipeptide was obtained as a white solid (900 mg, 93%) and was used in the next step without further purification. [ ⁇ ] D 20 -9.02 (c 1, MeOH).
- N-Boc-Tyr(Me)-Leu-OMe This compound was synthesized as described above from N- Boc-Tyr(Me)-OSu (1 g, 2.55 mmol), Leu-OMe.HCl (418 mg, 2.3 mmol) and NEt 3 (323 ⁇ L, 2.3 mmol). The dipeptide was obtained as a white solid (952 mg, 98%) and was used in the next step without further purification.
- N-Boc-Tyr(Me)-Asn-OMe This compound was synthesized as described above from N- Boc-Tyr(Me)-OSu (1 g, 2.55 mmol), HCl, Asn-OMe (417 nig, 2.3 mmol) and NEt 3 (323 ⁇ L, 2.3 mmol). The dipeptide was obtained as a white solid (653 mg, 67%) which was used in the next step without further purification.
- N ⁇ Boc-Tyr(Bn)-Gly-OMe Same procedure as for N-Boc-Tyr(Bn)- AIa-OMe with N-Boc- Tyr(Bn)-OSu (1 g, 2.13 mmol), Gly-OMe.HCl (268 mg, 2.14 mmol) and NEt 3 (0.3 niL, 2.16 mmol) in DMF (4 mL).
- the dipeptide was obtained as a white solid (946 mg, 100%) which was used in the next step without further purification. Recristallization of dipeptide from hot iso-propanol afforded an analytical sample, mp 118-120 °C (litt 118-120 0 C Flouret, G.
- N-Boc-Tyr(Bn)-Arg(Z) 2 -OH Same procedure as above with N-Boc-Tyr(Bn)-Osu (837 mg, 1.78 mmol), H-Arg(Z) 2 -OH (791 mg, 1.78 mmol) in DMF (10 mL). The reaction mixture was stirred for 4 days followed by usual work-up. The dipeptide was isolated after precipitation in CH 2 Cl 2 /pentane (972 mg, 68%).
- N-Boc-Tyr(Bn)-Lys(Boc)-OH Same procedure as above with N-Boc-Tyr(Bn)-OSu (1 g, 2.13 mmol), H-Lys(Boc)-OH (550 mg, 2.23 mmol) and a few drops Of NEt 3 in DMF (3.5 mL). The dipeptide was isolated after precipitation in CH 2 Cl 2 /pentane (946 mg, 74%). mp 168-170 0 C.
- N-Boc-Tyr(Bn)-Gly-OH A solution Of N-BoC-TyT(Bn)-GIy-OMe (500 sag, 1.13 mmol) in THF (1.4 mL) was treated with aqueous LiOH (1 M, 1.4 niL, 1.4 mmol) at O 0 C for lh30. The reaction mixture was quenched with aqueous 4 N HCl. The aqueous phase was extracted with CH 2 Cl 2 . The combined organic phases were dried over Na 2 SO 4 and concentrated in vacuo to give crude carboxylic acid (435 mg, 89%) which was taken in the next step without further purification, mp 157-159 °C.
- N-Boc-Tyr(Bn)- AIa-OH Same procedure as above with N-Boc-Tyr(Bn)-Ala-OMe (1.55 g, 3.39 mmol), aqueous LiOH (1 M, 4 mL, 4 mmol) in THF (4 mL). A white solid was obtained (1.25 g, 83%) which was used in the next step without further purification.
- N-Boc-Tyr(Bn)-Leu-OH Same procedure as above with N-Boc-Tyr(Bn)-Leu-OMe (1.034 g, 2.073 mmol), aqueous LiOH (1 M, 2.2 mL, 2.2 mmol) in THF (15 mL). A white solid was obtained (1.035 g, 100%) which was used in the next step without further purification.
- N-Boc-Tyr(Bn)-Asn-OH Same procedure as above with N-Boc-Tyr(Bn)-Asn-OMe (1.035 g, 2.072 mmol), aqueous LiOH (1 M, 2.2 mL, 2.2 mmol) in THF (15 mL). A beige solid was obtained (1.03 g, 100%) which was used in the next step without further purification.
- Bromo, iodo tripeptides were prepared according to Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J., Synthesis of macrocyclic peptide analogues of proteasome inhibitor TMC-95A. J. Org. Chem. 2003, 68, (25), 9835-9838.
- N-Boc-3-iodo-Tyr(Bn)-Leu-7-bromo-Trp-OEt compound Al 74.
- the peptide coupling was performed in CH 2 Cl 2 (0.5 mL) using 7-bromo-Trp-OEt (15 mg, 0.048 mmol), crude N- Boc-3-iodo-Tyr(Bn)-Leu-OH (31 mg, 0.05 mmol), EDC (11 mg, 0.053 mmol), HOBt (8 mg, 0.053 mmol) and NEt 3 (15 ⁇ L, 0.1 mmol).
- N-Boc-3-iodo-Tyr(Me)-AIa-7-bromo-Trp-OMe compound A385: The peptide coupling was performed in CH 2 Cl 2 (1.5 mL) using 7-bromo-Trp-OMe (100 mg, 0.3 mmol), crude N- Boc-3-iodo-Tyr(Me)- AIa-OH (148 mg, 0.3 mmol), EDC (63 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol) and NEt 3 (93 ⁇ L, 0.66 mmol).
- N-Boc-3-iodo-Tyr(Bn)-Ala-7-bromo-Trp-OH compound A215.
- a solution of N-3- iodo-Tyr(Bn)-Ala-7-bromo-Trp-Ome (85.5 mg, 0.100 mmol) in THF (0.4 mL) was treated at 0 0 C by 1 M aqueous NaOH (0.12 mL, 0.12 mmol). After 5 hours at room temperature, 1 M aqueous HCl was added (0.36 mL, 0.36 mmol). The resulting mixture was diluted by water and extracted by CH 2 Cl 2 (3 X 10 mL).
- N-Boc-3-iodo-Tyr(Me)-Leu-7-bromo-Trp-OEt compound A340.
- the peptide coupling was performed in CH 2 Cl 2 (3.7 mL) using 7-bromo-Trp-OEt (294 mg, 0.75 mmol), crude N- Boc-3-iodo-Tyr(Me)-Leu-OH (400 mg, 0.75 mmol), EDC (172 mg, 0.9 mmol), HOBt (121 mg, 0.9 mmol) and NEt 3 (230 ⁇ L, 1.65 mmol).
- N-Boc-3-iodo-Tyr(Bn)-A ⁇ a-7-bromo-Trp-NHMe compound A254.
- the peptide coupling was performed in CH 2 Cl 2 (4.4 mL) using HBr,7-bromo-Trp-NHMe (330 mg, 0.874 mmol), crude N-Boc-3-iodo-Tyr(Bn)-Ala-OH (521 mg, 0.918 mmol), EDC (124 mg, 0.96 mmol), HOBt (130 mg, 0.96 mmol) and NEt 3 (370 ⁇ L, 2.62 mmol).
- Macrocyclic peptides were prepared according to Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J., Synthesis of macrocyclic peptide analogues of proteasome inhibitor TMC-95A. J. Org. Chem. 2003, 68, (25), 9835-9838. A374F1 : described in the above article
- N-(tert-butoxycarbonyl)-3-[(4,4,5,5-tetramethyl-l,3,2-dioxaboroIane-2-yl)]-Tyr(Bn)- AIa-OMe A flame-dried Schlenk tube charged with Boc-4iodoTyr(Bn)-Ala-OMe (1.47 g, 2.53 mmol), KOAc (946 mg, 9.64 mmol), bis(pinacolato)diboron (773 mg, 3.04 mmol) and Pd(d ⁇ pf)Cl 2 .CH 2 Cl 2 (166 mg, 8 mol %) was flushed with argon.
- the brown oil was purified by flash chromatography on silica gel (20-40% AcOEt/Heptane) to give an inseparable mixture of the aryl boronate N-(tert-butoxycarbonyl)-3-[(4,4,5,5-tetramethyl- l,3,2-dioxaborolane-2-yl)]-Tyr(Bn)-Ala-OMe (57.5% yield estimated by 1 H NMN) and the dipeptide Boc-Tyr(Bn)- AIa-OMe (939 mg, ca 7.8:1 ratio).
- Biaryl SP226F1 Same procedure as described above with a mixture of aryl boronate N- (tert-butoxycarbonyl)-3-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolane-2-yl)]-Tyr(Bn)-Leu-OMe and dipeptide Boc-Tyr(Bn)-Leu-OMe (4.2 : 1 ratio) (361 mg, 0.463 mmol), Z-7-bromoTrp- NHMe (191 mg, 0.44 mmol), P(o-tolyl) 3 (15.1 mg, 10 mol %), Pd(OAc) 2 (6.8 mg, 5 mol %) and 0.5 mL of an aqueous solution Of Na 2 CO 3 (1 mmol, 2 M) in degassed dioxane (3 mL).
- N-Boc-Tyr(Bn)-Ala-Trp-NHPh compound SP303r2.
- Trp-NHPh 202 mg, 0.723 mmol
- CH 2 Cl 2 ZDMF 3 mL, 1/1
- EDC 153.6 mg, 0.8 mmol
- HOBt 108 mg, 0.8 mmol
- N-Boc-Tyr(Bn)-Leu-Trp-NHPh compound A424P. Same procedure as above with Trp- NHPh (67.6 mg, 0.242 mmol), N-Boc-Tyr(Bn)-Leu-OH (117 mg, 0.242 mmol), EDC (49 mg, 0.25 mmol) and HOBt (35 mg, 0.25 mmol) in CH 2 C1 2 /DMF (3.6 mL, 1/1). The crude residue was dissolved in ether and precipitated with heptane to give a beige solid (135.6 mg, 75 %).
- N-Boc-Tyr(Bn)-Asn-Trp-NHPh compound SP314C2. Same procedure as above with Trp-NHPh (102.9 mg, 0.368 mmol), N-Boc-Tyr(Bn)-Asn-OH (178.9 mg, 0.368 mmol), EDC (78.2 mg, 0.41 mmol) and HOBt (55 mg, 0.41 mmol) in CH 2 Cl 2 ZDMF (1.5 niL, 1/1). The crude residue was purified by flash column chromatography on silica gel (0-5% MeOH/CH 2 Cl 2 ) to give an off-white solid (82.8 mg, 30 %).
- N-Boc-Tyr(Bn)-Arg(Z) 2 -Trp-NHPh compound SP310C. Same procedure as above with Trp-NHPh (100 mg, 0.358 mmol), N-Boc-Tyr(Bn)-Arg(Z) 2 -OH (286 mg, 0.359 mmol), EDC (75.8 mg, 0.395 mmol) and HOBt (53.4 mg, 0.395 mmol) in CH 2 C1 2 /DMF (1.8 mL, 1/1). The crude residue was purified by flash column chromatography on silica gel (0-1% MeOHZCH 2 Cl 2 ) to give a yellow solid (157.4 mg, 41%).
- N-Boc-Tyr(Bn)-Lys(Boc)-Trp-NHPh compound SP306P. Same procedure as above with Trp-NHPh (99.6 mg, 0.356 mmol), N-Boc-Tyr(Bn)-Lys(Boc)-OH (214 mg, 0.356 mmol), EDC (75.3 mg, 0.392 mmol) and HOBt (53.7 mg, 0.397 mmol) in CH 2 Cl 2 ZDMF (1.5 mL, 1/1). The crude residue was triturated with MeOH/pentane to afford a white solid (193.5 mg, 63%).
- N-Boc-Tyr(Bn)-Ala-Trp-NHCH 2 Ph compound SP304R. Same procedure as above with Trp-NHCH 2 Ph (194.5 nig, 0.663 mmol), N-Boc-Tyr(Bn)-Ala-OH (293.5 mg, 0.663 mmol), EDC (141.5 mg, 0.73 mmol) and HOBt (99 mg, 0.73 mmol) in CH 2 C1 2 /DMF (2.8 mL, 1/1). The crude residue was triturated with Et 2 ⁇ /pentane to afford a white solid (215.5 mg, 45%).
- N-Boc-Tyr(Bn)-Leu-Trp-NHCH 2 Ph compound A414P. Same procedure as above with Trp-NHCH 2 Ph (136.8 mg, 0.467 mmol), N-Boc-Tyr(Bn)-Leu-OH (227 mg, 0.467 mmol), EDC (94 mg, 0.49 mmol) and HOBt (66 mg, 0.49 mmol) in CH 2 Cl 2 (5 mL). The reaction mixture was diluted by CH 2 Cl 2 , washed with 2M aqueous Na 2 CO 3 , then 5% aqueous KHSO 4 and water.
- N-Boc-Tyr(Bn)-Arg(Z) 2 -Trp-NHCH 2 Ph compound SP31SC2. Same procedure as above with Trp-NHCH 2 Ph (139 mg, 0.474 mmol), N-Boc-Tyr(Bn)-Arg(Z) 2 -OH (378 mg, 0.474 mmol), EDC (100.2 mg, 0.523 mmol) and HOBt (70.8 mg, 0.523 mmol) in CH 2 C1 2 /DMF (3 mL, 1/1).
- N-Boc-Tyr(Bn)-Lys(Boc)-Trp-NHCH 2 Ph compound SP307P. Same procedure as above with Trp-NHCH 2 Ph (120.7 mg, 0.411 mmol), N-Boc-Tyr(Bn)-Lys(Boc)-OH (246.9 mg, 0.411 mmol), EDC (87.1 mg, 0.45 mmol) and HOBt (62.1 mg, 0.46 mmol) in CH 2 C1 2 /DMF (1.8 mL, 1/1). The crude residue was triturated with MeOH/pentane to afford a white solid (243 mg, 67%).
- N-Boc-Tyr(Bn)-Asn-Trp-NHCH2Ph compound A416. Same procedure as above with Trp-NHCH 2 Ph (63.03 mg, 0.215 mmol), N-Boc-Tyr(Bn)-Asn-OH (105.0 mg, 0.216 mmol), EDC (44 mg, 0.226 mmol) and HOBt (31 mg, 0.226 mmol) in CH 2 Cl 2 ZDMF (1.5 mL/1.5 mL). After treatment, the crude residue was triturated with CH 2 Cl 2 /pentane to afford a white solid (78 mg, 48%).
- N-Boc-Tyr(Bn)-Gly-Trp-NHCH 2 Ph compound PSVIlR. Same procedure as above with Trp-NHCH 2 Ph (82.43 mg, 0.281 mmol), N-Boc-Tyr(Bn)-Gly-OH (109.26 mg, 0.255 mmol), EDC (53.87 mg, 0.281 mmol) and HOBt (37.97 mg, 0.281 mmol) in CH 2 C1 2 /DMF (2 mL/0.8 mL). The crude residue was triturated with CH 2 Cl 2 / ⁇ entane to afford a white solid
- N-Boc-Tyr(Bn) ⁇ Ala-Trp-NH(4-OH)Ph compound SP313P. Same procedure as above with Trp-NHPhOH (75 mg, 0.254 mmol), N-Boc-Tyr(Bn)-Ala-OH (106.4 mg, 0.24 mmol), EDC (53.8 mg, 0.28 mmol) and HOBt (37.9 mg, 0.28 mmol) in CH 2 Cl 2 ZDMF (1.5 mL, 1/1). The crude residue was triturated with Et 2 O to afford a pale brown solid (72.8 mg, 42%).
- N-Boc-Tyr(Bn)-Leu-Trp-NH(4-OH)Ph compound A418P. Same procedure as above with Trp-NH(4-OH)Ph (58.99 mg, 0.2 mmol), N-Boc-Tyr(Bn)-Leu-OH (97 mg, 0.2 mmol), EDC (41 mg, 0.21 mmol) and HOBt (29 mg, 0.21 mmol) in CH 2 Cl 2 ZDMF (3 mL IZl). The reaction mixture was diluted by CH 2 Cl 2 , washed with 2M aqueous Na 2 CO 3 , then 5% aqueous KHSO 4 and water.
- N-Boc-Tyr(Bn)-Asn-Tr ⁇ -NH(4-OH)Ph compound SP318C. Same procedure as above with Trp-NHPh-OH 149c (104.4 mg, 0.353 mmol), N-Boc-Tyr(Bn)-Asn-OH 147c (171.3 mg, 0.353 mmol), EDC (74.9 mg, 0.39 mmol) and HOBt (52.6 mg, 0.39 mmol) in CH 2 Cl 2 ZDMF (2.2 mL, 1/1).
- N-Boc-Tyr(Bn)-Arg(Z) r Trp-NH(4 ⁇ OH)Ph Trp-NH(4 ⁇ OH)Ph .
- compound SP320P2 Same procedure as above with Trp-NHPhOH (112 mg, 0.357 mmol), N-Boc-Tyr(Bn)-Arg(Z) 2 -OH (282 mg, 0.355 mmol), EDC (74.8 mg, 0.389 mmol) and HOBt (53.3 mg, 0.394 mmol) in CH 2 Cl 2 ZDMF (2.2 mL, 1/1). The crude residue (235.8 mg) was purified by flash column chromatography on silica gel (1-2% MeOH/CH 2 Cl 2 ) to give a yellowish solid (76.2 mg, 20%).
- N-Boc-Tyr(Bn)-Lys(Boc)-Trp-NH(4-OH)Ph compound SP319P. Same procedure as above with Trp-NHPhOH (75 mg, 0.239 mmol), N-Boc-Tyr(Bn)-Lys(Boc)-OH (143 mg, 0.238 mmol), EDC (50.6 mg, 0.264 mmol) and HOBt (35.3 mg, 0.261 mmol) in CH 2 Cl 2 ZDMF (1.6 mL, 1/1). The crude residue was triturated with MeOH/pentane to afford a white solid (142.5 mg, 68%).
- N-Boc-Tyr(Bn)-Ala-Trp-NH(CH 2 ) 4 NHBoc compound SP305R. Same procedure as above with Trp-NH(CH 2 ) 4 NHBoc (204.6 mg, 0.546 mmol), N-Boc-Tyr(Bn)-Ala-OH (242 mg, 0.546 mmol), EDC (116 mg, 0.61 mmol) and HOBt (82.2 mg, 0.61 mmol) in CH 2 C1 2 /DMF (2.2 mL, 1/1). The crude tripeptide (282 mg) can be recristallized from hot THF to give a white solid as an analytical sample (89.1 mg, 31.5%).
- N-Boc-Tyr(Bn)-Leu-Trp-NH(CH 2 ) 4 NHBoc compound SP296P. Same procedure as above with Trp-NH(CH 2 ) 4 NHBoc (264.7 mg, 0.706 mmol), N-Boc-Tyr(Bn)-Leu-OH (342.6 mg, 0.707 mmol), EDC (150.3 mg, 0.784 mmol), HOBt (105.3 mg, 0.78 mmol) and NEt 3 (0.39 mL, 2.8 mmol) in CH 2 C1 2 /DMF (3 mL, 1/1). The crude residue was triturated with Et 2 O/pentane to give a white solid (196.7 mg, 33%).
- N-Boc-Tyr(Bn)-Asn-Trp-NH(CH 2 ) 4 NHBoc compound SP323C2.
- Trp-NH(CH 2 ) 4 NHBoc 108.7 mg, 0.29 mmol
- N-Boc-Tyr(Bn)-Asn-OH 140.9 mg, 0.29 mmol
- EDC 61.8 mg, 0.32 mmol
- HOBt 43.6 mg, 0.32 mmol
- N-Boc-Tyr(Bn)-Arg(Z) 2 -Trp-NH(CH 2 ) 4 NHBoc compound SP311C. Same procedure as above with Trp-NH(CH 2 ) 4 NHBoc (105.7 mg, 0.282 mmol), N-Boc-Tyr(Bn)-Arg(Z) 2 -OH (224.5 mg, 0.282 mmol), EDC (59.5 mg, 0.31 mmol) and HOBt (42.5 mg, 0.31 mmol) in CH 2 Cl 2 ZDMF (1.8 mL, 1/1).
- N-Boc-Tyr(Bn)-Lys(Boc)-Trp-NH(CH 2 ) 4 NHBoc compound SP308P. Same procedure as above with Trp-NH(CH 2 ) 4 NHBoc (152.4 mg, 0.407 mmol), N-Boc-Tyr(Bn)-Lys(Boc)-OH (247.3 mg, 0.407 mmol), EDC (85.8 mg, 0.45 mmol) and HOBt (60.7 mg, 0.45 mmol) in CH 2 C1 2 /DMF (1.8 mL, 1/1). The crude residue was triturated with MeOH/pentane to afford a white solid (255.9 mg, 65%).
- N-Boc-Tyr-Arg-Trp-NHCH 2 Ph compound SP325.
- a solution of N-Boc-Tyr(Bn)- Arg(Z 2 )-Trp-NHCH 2 Ph (86.15 mg, 0.0804 mmol) in MeOH/DMF (1.4 mL, 1/0.4) was hydrogenated at atmospheric pressure over 10% Pd on charcoal (9.14 mg) for 18 h.
- the mixture was filtered over a pad of celite and concentrated.
- the resulting residue was triturated in Et 2 O and filtered to afford the product as a white solid (46.55 mg, 81 %).
- N-Boc-Tyr-Arg-Trp-NH(4-OH)Ph compound SP324. Same procedure as above using N-Boc-Tyr(Bn)-Arg(Z 2 )-Trp-NH(4-OH)Ph (60.81 mg, 0.0567 mmol), 10% Pd on charcoal (6.43 mg) in MeOH/DMF (0.8 mL, 7/1) and affording N-Boc-Tyr-Arg-Tr ⁇ -NH(4-OH)Ph as a beige solid (34.89 mg, 86 %).
- N-Boc-Tyr(Bn)-Gly-Trp-OH compound NR35. Saponification of N-Boc-Tyr(Bn)-Gly- Trp-OMe (242 mg, 0.385 mmol) in THF (0.5 mL) by 1 M aqueous LiOH (0.5 mL, 0.5 mmol) afforded after acidic treatment and precipitation of the residue with CH 2 Cl 2 /pentane N-Boc- Tyr(Bn)-Gly-Trp-OH as a white solid.
- N-Boc-Tyr(Bn)-Ala-Trp-OCH 3 compound NR36. Same procedure as above with HCl, Trp-OCH 3 (255 mg, 1 mmol), N-Boc-Tyr(Bn)-Ala-OH (444 mg, 1 mmol), DCC (259 mg, 1.26 mmol) and HOBt (172 mg, 1.27 mmol) in THF (15 mL). The crude residue was chromatographed over silica gel to afford a white solid (361 mg, 56%).
- N-Boc-Tyr-Ala-Trp-OCH 3 compound NR40.
- N-Boc-Tyr(Bn)-Ala-Trp-OMe (119 mg, 0.185 mmol) in solution in MeOH (4 mL) was hydrogenated overnight at atmospheric pressure in the presence of 10% Pd on charcoal (30 mg). After f ⁇ ltation, evaporation of the solvant and trituration with ether, N-Boc-Tyr-Ala-Trp-OMe (77 mg, 76 %) was obtained as a solid.
- N-Boc-Tyr(Bn)-Ala-Trp-OH compound NR66. Saponification of N-Boc-Tyr(Bn)-Ala- Trp-OMe (580 mg, 0.902 mmol) in THF (5 mL) by 1 M aqueous LiOH (2 mL, 2 mmol) at 4 0 C for 1 hour, afforded after acidic treatment and precipitation of the residue with water crude N-Boc-Tyr(Bn)-Gly-Trp-OH. The crude product in MeOH (0.5 mL) was treated by dicyclohexylamine (0.18 mL, 0.91 mmol) and then ether (10 mL).
- N-Boc-Tyr-Ala-Trp-OH compound NR68.
- N-Boc-Tyr(Bn)-Ala-Trp-OH 233 mg, 0.37 mmol
- MeOH MeOH
- Pd on charcoal 40 mg
- N-Boc-Tyr-Ala-Trp-OMe was obtained as a solid (152 mg, 76 %).
- Boc-Tyr(Bn) -Arg(Z) 2 -Trp[O]-NHPh compound CVIl.
- Boc-Tyr(Bn) -Arg(Z) 2 -Trp[O]-NHPh was obtained as a white solid (262 mg, 37 %).
- Boc-Tyr(Bn)-Ala-Trp [O]-NHPh compound CV13.
- Boc-Tyr(Bn)-Leu-Trp [O]-NHPh compound JV602.
- the general procedure starting from Boc-Tyr(Bzl)-Leu-OH (109.5 mg, 0.226 mmol), HOBt ( 36.38 mg, 0.269 mmol), EDC, HCl (50.29, 0.262 mmol) and Trp[O]-NHPh (66.32 mg, 0.224 mmol) afforded the crude tripeptide as a solid which was suspended in boiling water (4 mL).
- Boc-Tyr(Bn)-Lys(Boc)-Trp [O]-NHPh compound CV12.
- Boc-Tyr(Bn)-Gly-Trp[0]-NHCH 2 Ph compound NR15.
- Boc-Tyr(Bn) -Arg(Z) 2 -Trp [O] -NHCH 2 Ph compound NR16.
- Boc-Tyr(Bn)-GIy-Trp[0]-OCH 3 compound NR38.
- Boc-Tyr(Bn)-Ala-Trp[0]-OCH 3 The general procedure starting from dipeptide Boc- Tyr(Bn)-Ala-OH, HOBt, EDC, HCl and Trp[O]-OMe afforded, after chromatography over silica gel the tripeptide Boc-Tyr(Bn)-Ala-Trp [O]-OMe.
- Boc-Tyr(Bn)-Ala-Trp [O]-OH Saponification of Boc-Tyr(Bn)-Ala-Trp[O]-OMe in THF with aqueous LiOH afforded after acidification with aqueous HCl, Boc-Tyr(Bn)-Ala-Trp[O]- OH.
- Boc-Tyr-AIa-Trp[0]-OCH 3 Stirring of a mixture of Boc-Tyr(Bn)-Ala-Trp[O]-OMe and 10% Pd / C under atmosphere of hydrogene afforded Boc-Tyr-Ala-Trp[O]-OMe
- Boc-Tyr-Ala-Trp [O]-OH Stirring of a mixture of Boc-Tyr(Bn)-Ala-Trp [O]-OH and 10% Pd / C under atmosphere of hydrogene afforded Boc-Tyr-Ala-Trp[O]-OH
- N-Boc-3-iodo-Tyr(Me)-OMe To a stirred suspension of I 2 (370 mg, 1.46 mmol) and Ag 2 SO 4 (455 mg, 1.46 mmol) in MeOH (24 mL) was added Boc-Tyr(Me)-OMe (376 mg, 1.22 mmol) at room temperature. The mixture was stirred for 1 h. The yellow solid was removed by filtration over celite and the filtrate was concentrated off. The residue was dissolved in CHCl 3 and washed successively with aqueous 0.1 M Na 2 S 2 O 3 , water and brine. The organic layer was dried over Na 2 SO 4 and the solvent was evaporated under vacuum.
- N-Boc-3-iodo-Tyr(Me)- ⁇ Ala-OH To the crude N-Boc-3-iodo-Tyr(Me)-OH (2.53 g, 6 mmol) in DME (12 niL) cooled at O 0 C was added DCC (1.32 g, 6.4 mmol) and SuOH (0.74 g, 6.4 mmol). The mixture was allowed to warm up overnight before filtration of the DCU precipitate. Washing of the solid with AcOEt and evaporation of the filtrate afforded the activated tyrosine ester (3 g, 100%) which was used in the next step without further purification.
- N-Boc-3-iodo-Tyr(Me)- ⁇ Ala-7-bromo-Trp-OMe compound A493.
- N-Boc-3-iodo-Tyr(Me)- ⁇ Ala-OH 81 mg, 0.24 mmol
- Boc-3-iodo-Tyr(Me)-OH 120 mg
- NH 2 -(Bn)AIa-OMe hydrochloride salt BocNH-(Bii)Ala (200 mg, 0.68 mmol prepared according to Hannachi, J. C; Vidal, J.; Mulatier, J. C; Collet, A., Electrophilic animation of amino acids with N-Boc-oxaziridines: efficient preparation of N-orthogonally diprotected hydrazino acids and piperazic acid derivatives. J. Org. Chem. 2004, 69, (7), 2367-2373) was solubilized in a 4.5 M anhydrous HCl solution in MeOH. The mixture was allowed to stir overnight and concentrated off.
- N-Boc-3-iodo-Tyr(Me)-NH-(Bn)AIa-OMe To a suspension of HCl, NH 2 -(Bn)AIa-OMe (100 mg, 0.41 mmol), Boc-3-iodo-Tyr(Me)-OH (172 mg, 0.41 mmol) and PyBOP (213 mg, 0.41 mmol) HOBt (37 mg, 0.27 mmol) in CH 2 Cl 2 (1 mL) was added DIEA (196 ⁇ L, 1.13 mmol) at 0 0 C. The resulting solution was allowed to warm up and was stirred for 2 h.
- reaction mixture was diluted in AcOEt and washed successively with aqueous 5% KHS 04, aqueous 0.5 M KHCO 3 and brine.
- the organic layer was dried over Na 2 SO 4 and the solvent was removed in vacuo.
- the residue was subjected to flash chromatography on silica gel (30% AcOEt/cyclohexane) to afford N-Boc-3-iodo-Tyr(Me)-NH-(Bn) AIa-OMe (165 mg, 66%) as a white amorphous solid.
- N-Boc-Tyr(Me)-NH-(Bn)Ala-Trp-OMe Treatment of N-Boc-3-iodo-Tyr(Me)-NH-(Bn) Ala-7-bromo-Trp-OMe in the condition of the suzuki coupling according to Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J., Synthesis of macrocyclic peptide analogues of proteasome inhibitor TMC-95A. J. Org. Chem. 2003, 68, (25), 9835-9838 afforded N-Boc-Tyr(Me)- NH(Bn)Ala-Trp-OMe.
- HRMS (ESI) calcd for C 37 H 45 N 5 O 7 Na [(M+Na) + ] 694.3217, found 694.3197.
- N-Boc-Tyr(Me)- ⁇ AIa-Trp-OMe Treatment of N-Boc-3-iodo-Tyr(Me)- ⁇ Ala-7-bromo- Trp-OMe in the condition of the suzuki coupling according to Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J., Synthesis of macrocyclic peptide analogues of proteasome inhibitor TMC-95A. J. Org. Chem. 2003, 68, (25), 9835-9838 afforded N-Boc-Tyr(Me)- ⁇ Ala-Trp- OMe.
- HRMS (ESI) calcd for C 30 H 38 N 4 O 7 Na [(M+Na) + ] 589.2638, found 589.2634.
- 2OS proteasome from rabbit reticulocyte was from commercial source (Alexis Biochemicals)
- the buffers were: 20 mM Tris, 1 mM DTT, 10 % glycerol, 3 % (v/v) DMSO (ChT-L and PA activities) ; 20 mM Tris, 1 mM DTT, 10 % glycerol, 3 % (v/v) DMSO. Studied compounds were dissolved in DMSO prior dissolution in the buffer. Proteasome was incubated for 15 min at 30 0 C in the presence of the studied compound (0.1- 100 ⁇ M). A control assay in the absence of tested compounds contained DMSO at the same concentration (3 %, v/v).
- Figure 1 Schematic representation of the reaction of: (A) peptidic inhibitors
- Adducts (A) or stable acyl-enzymes (B) are obtained after the formation of a covalent bond between Thrl and the reactive group of the inhibitor.
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US11/918,060 US7919468B2 (en) | 2005-04-07 | 2005-12-22 | Compounds useful as modulators of the proteasome activity |
EP05848937.8A EP1865950B1 (fr) | 2005-04-07 | 2005-12-22 | Composes convenant comme modulateurs de l'activite du proteasome |
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
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KR100842351B1 (ko) * | 2007-01-04 | 2008-06-30 | 한국생명공학연구원 | 인돌 유도체를 유효성분으로 함유하는 암 예방 및 치료용약학적 조성물 |
US8530623B2 (en) | 2009-04-02 | 2013-09-10 | Isp Investments Inc. | Proteasome-activating lightening peptides and compositions containing same |
US8530622B2 (en) | 2009-04-02 | 2013-09-10 | Isp Investments Inc. | Proteasome-activating anti-aging peptides and compositions containing same |
US8546335B2 (en) | 2009-04-23 | 2013-10-01 | Isp Investments Inc. | Peptidic hydrolyzate proteasome activators and compositions containing same |
WO2014056954A1 (fr) * | 2012-10-12 | 2014-04-17 | F. Hoffmann-La Roche Ag | Inhibiteurs macrocycliques de cétoamide immunoprotéasome |
US8722627B2 (en) | 2009-04-23 | 2014-05-13 | Isp Investments Inc. | Proteasome-activating lightening peptidic hydrolyzates and compositions containing them |
US8883734B2 (en) | 2009-04-02 | 2014-11-11 | Isp Investments Inc. | Proteasome-activating anti-aging peptides and compositions containing same |
EP3178836A1 (fr) * | 2009-10-22 | 2017-06-14 | Imperial Innovations Limited | Agents de ciblage gadd45beta |
Families Citing this family (2)
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WO2013025986A2 (fr) | 2011-08-17 | 2013-02-21 | Basf Corporation | Principes actifs cosmétiques d'origine marine et leur utilisation |
CN111170923B (zh) * | 2018-11-13 | 2023-07-25 | 上海市伤骨科研究所 | 一类dl-色氨酸类化合物、其制备方法及用途 |
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- 2005-12-22 EP EP05848937.8A patent/EP1865950B1/fr not_active Not-in-force
- 2005-12-22 WO PCT/EP2005/013893 patent/WO2006105811A1/fr not_active Application Discontinuation
- 2005-12-22 US US11/918,060 patent/US7919468B2/en not_active Expired - Fee Related
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EP0248231A2 (fr) * | 1986-05-31 | 1987-12-09 | Brantl, Victor, Dr. med., Dipl.-Chem. | Peptides à activité pharmacologique |
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US8530622B2 (en) | 2009-04-02 | 2013-09-10 | Isp Investments Inc. | Proteasome-activating anti-aging peptides and compositions containing same |
US8883734B2 (en) | 2009-04-02 | 2014-11-11 | Isp Investments Inc. | Proteasome-activating anti-aging peptides and compositions containing same |
US8546335B2 (en) | 2009-04-23 | 2013-10-01 | Isp Investments Inc. | Peptidic hydrolyzate proteasome activators and compositions containing same |
US8722627B2 (en) | 2009-04-23 | 2014-05-13 | Isp Investments Inc. | Proteasome-activating lightening peptidic hydrolyzates and compositions containing them |
EP3178836A1 (fr) * | 2009-10-22 | 2017-06-14 | Imperial Innovations Limited | Agents de ciblage gadd45beta |
WO2014056954A1 (fr) * | 2012-10-12 | 2014-04-17 | F. Hoffmann-La Roche Ag | Inhibiteurs macrocycliques de cétoamide immunoprotéasome |
CN104854124A (zh) * | 2012-10-12 | 2015-08-19 | 弗·哈夫曼-拉罗切有限公司 | 大环酮酰胺免疫蛋白酶体抑制剂 |
US20150266920A1 (en) * | 2012-10-12 | 2015-09-24 | Hoff-Mann-La Roche Inc. | Macrocyclic ketoamide immunoproteasome inhibitors |
Also Published As
Publication number | Publication date |
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EP1865950A1 (fr) | 2007-12-19 |
US7919468B2 (en) | 2011-04-05 |
CA2604133C (fr) | 2015-12-01 |
EP1865950B1 (fr) | 2013-08-28 |
US20090069222A1 (en) | 2009-03-12 |
CA2604133A1 (fr) | 2006-10-12 |
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